The ends of linear chromosomes are capped by telomeres. Human telomeres consist of repetitive two thymidine (TT), one adenine (A) and 3 glycine (GGG) subunits, which are associated with a variety of telomere-binding proteins known as the sheltering complex (Blackburn et al., 1994, de Lange et al., 2002).
Telomeres get progressively shorter with each cell division. This process occurs because the DNA-replication machinery is incapable of fully replicating the ends of linear molecules, and, degradation and oxidative damage of nucleotides in DNA. Telomerase is an enzyme, which has the ability to prevent telomeres from shortening although most of the cells do not express sufficient quantities of this enzyme to prevent this process. As a result, telomeres shorten with age in tissues and cells (Kenkichi et al., 2001, Harley et al., 2001, Huffman et al., 1990).
The function of telomeres is to mask and protect the ends of chromosomes from exposure to DNA damage. Telomeres maintain chromosome integrity. When telomere ends are unprotected, genomic instability is triggered. Genomic instability has been implicated as a major causal factor in cancer and aging (Charames et al., 2003, Holland et al., 2009, Hanialra et al., 2011).
Genomic instability is a crucial step in the development of most cancers. It has been suggested that inactivation of DNA repair pathways, which leads to an increased mutation rate and chromosomal instability, can initiate and accelerate the neoplastic process (Lothe et al., 1993, Rudolph et al., 1999, Colleu-Durel et al., 2001, Chan et al., 2002).
Genomic instability increases with age (Slagboom et al., 1999). There are a few potential mechanisms that have been proposed to explain age-dependent genome instability. These include the accumulation of oxidative damage to DNA, defects in mitochondrial functions that promote oxidative stress and DNA damage, mutations in proteins required for efficient DNA replication, DNA repair and checkpoints, telomere erosion and epigenetic effects on DNA repair and other genome maintenance programs (Hayflick et al., 1977, Sohal et al., 1985, Harley et al., 1990).
Telomeres become shorter during life. Accumulation of short telomeres in tissues contributes to pathological conditions such as congenital dyskeratosis, Werner premature aging syndrome and Alzheimer's disease (Yu et al., 1996, Shen et al., 1998, Fry et al., 1999, Burns et al., 2002, Panossian et al., 2003, Thomas et al., 2007).
Studies on telomere lengths in patients with Alzheimer's disease (AD) have revealed contrary results. Telomere shortening in AD seems to be cell type dependent (Panossian et al., 2003, Baird et al., 2004, Thomas et al., 2008). Short telomeres are found in cells such as lymphocytes, leukocytes, peripheral blood mononuclear cells, fibroblast cells, and buccal cells (BCs) from Alzheimer's patients (Jenkit et al., 2003, Panossian et al., 2003, Honig et al., 2006, Lukaset et al., 2009) whereas in brain tissue such as the hippocampus, telomeres have been found to be longer than in controls (Thomas et al., 2008). These findings indicate important differences in telomere maintenance in AD patients in different groups of cells.
AD is a neurodegenerative condition resulting in neuronal death. AD patients show symptoms of impaired memory, judgment and decision-making among other cognitive disabilities (Burns et al., 2002, Du et al., 2001). AD patients are currently diagnosed on clinical grounds while excluding other causes of dementia. The two histopathological structures present within the brain that positively identify AD conclusively at post-mortem are the neurofibrillary tangles and the amyloid-based neuritic plaques (Haroutunian et al., 1998, Matsson et al., 2000, Kawas et al., 2003).
Neurofibrillary tangles are composed of microtubule-associated hyperphosphorylated tau protein. Tau is associated with tubulin in the formation of microtubules. One function of microtubules is to provide points of attachment for chromosomes during cell division, which, if disrupted may result in an increased incidence of chromosome malsegregation and genomic instability (Iqbal et al., 1998, Petkova et al., 2002). The second histopathological feature of AD patients is the presence of amyloid-based neuritic plaques. 3-amyloid peptide (Aβ42) originates from the aberrant proteolysis of the amyloid precursor protein (APP) (Petkova et al., 2002, Antzutkin et al., 2002). The APP gene APP is located on chromosome 21. Aneuploidy of chromosomes 17 and 21 are common hallmarks of AD and genomic instability (Thomas et al., Mutagenesis 2008).
AD is an age related disease associated with genomic instability. Telomere shortening was studied in lymphocytes and fibroblasts in AD and age related healthy controls (Panossian et al., 2003, Cawthorn et al., 2003). A study by Thomas using PCR revealed a trend of shorter telomeres in AD samples compared to age matched controls (Thomas et al., 2008). Shorter telomeres were detected in peripheral blood mononuclear cells from AD patients (Honig et al., 2006, Thomas et al., 2008, Lukens et al., 2009).